(a) Field of the Invention
(b) Description of Prior Art
Bone growth into porous materials has proven to be a very effective method for attaching prosthetic implants to the bony skeleton (Engh C A, Claus A M, Hopper R H, Engh C A. Clin Orthop 393:137-146, 2001; Teloken M A, Bissett G, Hozack W J, Sharkey P F, Rothman R H. J Bone Joint Surg [Am] 84-A:2140-2144, 2002; D'Antonio J A, Capello W N, Manley M T, Geesink R. Clin Orthop 393:101-111, 2001; Pidhorz L E, Urban R M, Jacobs JJ, Sumner D R, Galante J O. J Arthrop 8:213-225, 1993; Sychterz C J, Claus A M, Engh C A. Clin Orthop 405:79-91, 2002). However, there remains a need to develop modalities that can accelerate and/or increase biologic fixation. The more rapid and the greater the amount of bone formation around and/or within an implant, the faster the implant becomes mechanically secured against the disruptive forces of load bearing and the sooner patients can safely return to their activities of daily living. In situations where bone stock is frequently compromised, or where initial implant stability is more tenuous (such as in the elderly, post-traumatic cases, or revision surgery), both short and long-term clinical results are inferior, and the construct would clearly benefit from enhanced biologic fixation. As well, the more extensive the peri-implant tissue formation, the more protected is the bone-implant interface against wear particle induced periprosthetic osteolysis (Bobyn J D, Jacobs JJ, Tanzer M, Urban R M, Aribindi R, Sumner R, Turner T, Brooks C E, Galante J O: Clin Orthop 311:21, 1995). Increased peri-implant bone formation may also minimize the risk of postoperative periprosthetic fractures and provide additional bone stock if a subsequent revision is needed. An additional issue relates to the bone-implant interface in the immediate post-operative phase. A likely scenario for the onset of prosthetic loosening is that initial implant fixation is compromised by the resorption of the traumatized and necrotic bone adjacent to the implant. This theory is supported by the quantitative radiostereometry studies of Ryd et al (Ryd L, Albrektsson B E, Carlsson L, et al: J Bone Joint Surg [Br] 77:377-83, 1995) that showed postoperative implant migration predicts later loosening. This early migration must be related to bone resorption, since oral bisphosphonate therapy has recently been shown to reduce the initial migration of knee prostheses through its inhibitory effect on osteoclastic function (Hilding M, Ryd L, Toksvig-Larsen S, Aspenberg P: Acta Orthop Scand 71:553-7, 2000).
Various methods have been investigated to increase the rate and/or the extent of bone growth into porous implants, with varying degrees of success. Due largely to practical limitations and/or cost issues, only calcium phosphate coatings, and most notably hydroxyapatite, have to date reached the point of clinical applications. (Geesink R. Clin Orthop 225:147-170, 1990; Bauer T W, Geesink R C, Zimmerman R, McMahon J T. J Bone Joint Surg [Am] 73:1439-1452, 1991; D'Antonio J A, Capello W N, Manley M T, Geesink R. Clin Orthop 393:101-111, 2001; Overgaard S, Bromose U, Lind M, Bunger C, Soballe K. J Bone Joint Surg [Br] 81:725-731, 1999) Of particular recent interest is the use of bisphosphonates for modifying bone remodeling around orthopaedic devices. Bisphosphonates selectively absorb to bone mineral and inhibit bone resorption by interfering with the action of osteoclasts. It is believed that bisphosphonates are internalized by osteoclasts, interfere with specific biochemical processes and induce apoptosis. All bisphosphonates contain two phosphonate groups attached to a single carbon atom, forming a P—C—P structure; as such they are stable analogues of naturally occurring pyrophosphate-containing compounds. The more potent nitrogen-containing bisphosphonates, such as zoledronic acid (ZA), may affect cellular activity and cell survival by interfering with protein prenylation and therefore the signaling functions of key regulatory proteins (Russell RGG, Rogers M J: Bone 25:97-106, 1999).
Recent literature has described the utility of bisphosphonates for affecting the osteoblastic/osteoclastic cellular response in both mature and healing bone (Green JR, Müller K, Jaeggi K A. J Bone Miner Res 9:745-751, 1994; Pataki A, Muller K, Green J R, Ma Y F, Li Q N, Jee W S. Anat Rec 249:458-468, 1997). This has resulted in oral bisphosphonate therapy for helping to mitigate the osteolytic effects of accumulated wear debris around joint replacement implants (Shanbhag A S, Hasselman C T, Rubash H E. Clin Orthop 344:33-43, 1997; Shanbhag A S, May D, Cha C, Kovach C, Hasselman C T, Rubash H E. Trans Orthop Res Soc 24:255, 1999; Horowitz, S M, Algan, S A, Purdon M A. J Biomed Mater Res 31:91-96, 1996.) As well, bisphosphonates have been used to manage periprosthetic bone loss as might occur through stress shielding mechanisms (Soininvaara T A, Jurvelin J S, Miettinen H J A, Suomalainen O T, Alhava E M, Kroger P J. Calcified Tissue Int 71:472-477, 2002; Venesmaa P K, Kroger H P, Miettinen H J, Jurvelin J S, Suomalainen O T, Alhava E M. J Bone Miner Res 16:2126-2131, 2001; Wilkinson J M, Stockley I, Peel N F, Hamer A J, Elson R A, Barrington N A, Eastell R. J Bone Miner Res 16:556-564, 2001). Also of important note is that Hilding et al (Hilding M, Ryd L, Toksvig-Larsen S, Aspenberg P: Acta Orthop Scand 71:553-7, 2000) showed an early postoperative oral regimen of clodronate reduced migration of knee prostheses, as measured by radiostereometry. In experimental rabbit studies, Little et al (Little DG, Cornell M S, Briody J, Cowell C T, Arbuckle S, Cooke-Yarborough C M. J Bone Joint Surg [Br] 83-B:1069-1074, 2001) have shown that in distraction osteogenesis a single postoperative intravenous dose of pamidronate (3 mg/kg) decreased the disuse osteopenia normally associated with lengthening and increased the amount and density of the regenerate bone. In a further study, Little et al (Little DG, Smith N C, Williams P, Briody J, Bilston, L, Smith EJ, Gardiner E M, Cowell C T. J Bone Miner Res 18:1300-1307, 2003) showed that one or two doses of the more potent ZA abolished osteopenia and increased regenerate volume, mineralization and strength.
There has been speculation about the possibility of bisphosphonates acting not only to suppress osteoclastic activity but also to stimulate osteoblastic activity (Green J R, Muller K, Jaeggi K A. J Bone Miner Res 9:745-751, 1994; Pataki A, Müller K, Green J R, Ma Y F, Li Q N, Jee W S. Anat Rec 249:458-468, 1997; Shanbhag A S, Kenney J, Manning C, Flannery M, Rubash H, Harris W, Goldring S. Trans Orthop Res Soc 25:688, 2000). However, recent findings by Smith et al (Smith EJ, Bugler R J, Peat R A, McEvoy A, Briody J N, Baldock P A, Eisman J A, Little DG, Gardiner E M. Trans Orthop Res Soc 28:351, 2003) have shown that the increase in net bone accumulation from ZA were due to an increase in retention of callus; the bone formation rate was actually reduced. Modulation of bone turnover shifted the balance of formation and resorption in a favorable manner resulting in a net increase in total regenerate at six weeks. Remodeling took place over 45 weeks in this model, indicating that the effects of ZA are long lasting.
On a cost basis alone, bisphosphonates could have a substantial advantage over recombinant proteins for improving the bone healing response within and around orthopaedic implants. Although intravenous delivery of ZA is both feasible and convenient, it subjects the patient to various systemic and potentially adverse effects.
Local delivery of medicinal products for implants of various types has been attempted, however with varying degrees of success. For example, anti-inflammatory agents delivered to coronary stent implant sites have been shown to increase patency rates. Local delivery of bisphosphonates in dental surgical applications has also recently been attempted. For example, local application of alendronate, a second generation bisphosphonate, following periodontal surgery in rats has been shown to reduce alveolar bone resorption. (Binderman I, Adut M, Yaffe A: J Periodontol 71:1236-40, 2000; Yaffe A, lztkovich M, Earon Y, Alt I, Lilov R, Binderman: J Periodontol 68:884-9, 1997) Another rat study has further shown that a single application of alendronate via a sponge to an implant site reduces the amount of soft tissue that forms as a consequence of resorptive remodeling from repetitive implant motion (Astrand J, Aspenberg P: J Orthop Res 22:244-249, 2004).
The concept of immobilizing a bisphosphonate compound via hydroxyapatite has previously been explored for dental surgical applications, particularly in the context of smooth surface tooth root implants. (Meraw S J and Reeve C M., Qualitative analysis of peripheral pen-implant bone and influence of alendronate sodium on early bone regeneration, J Peridontology 70:1228-1233, 1999; Yoshinari M, et al., Bone response to calcium phosphate-coated and bisphosphonate-immobilized titanium implants, Biomaterials 23:2879-2885, 2002; Ganguli A, et al, The interaction of bisphosphonates in solution and as coatings on hydroxyapatite with osteoblasts, J Mater Sci: Mater Med 13:923-931, 2002; Denissen H, et al, Normal osteoconduction and repair in and around submerged highly bisphosphonate-complexed hydroxyapatite implants in rat tibiae, J Periodontology 71:272-278, 2000). These studies have shown that local release of bisphosphonate compounds, bound to dental implants through an intermediary hydroxyapatite coating, results in a net gain in peri-implant bone formation. However, the extent of bone formation around the bisphosphonate coated implants shown by these studies remains relatively low compared to the control specimens. Therefore, however positive, relatively limited benefits with respect to bone formation have resulted.
Therefore, while the local delivery of bisphosphonate to an implant site for improving the bone healing response within and around the implant is desirable, the means by which the medicinal compounds are locally administered poses challenges for many implant applications. As such, a need exists for an improved means and method for administering a local release of bisphosphonate to allow the compound to positively affect peri-implant bone remodeling, while avoiding the systemic exposure. . Further, a need exists to improve the extent of bone formation by such locally released bisphosphonate.
It would therefore be highly desirable to be provided with a new implant improving bone formation around and/or within the implant.